This invention relates to the field of organic compounds. More particularly, this invention relates to the synthesis of certain chlorinated pyrimidines such as 4,6-dichloropyrimidine. In general, synthesis of chlorinated pyrimidines according to the present invention is accomplished by reacting imidoyl chlorides with phosgene.
Chlorinated pyrimidines prepared by the process of the present invention and, in particular 4,6-dichloropyrimidine, are known as useful compounds in the synthesis of many biologically active compounds. Use of such chlorinated pyrimidines in production of such varied compositions as pesticides and pharmaceuticals makes them economically important compounds as well. For example, 4,6-dichloropyrimidine can be used in the manufacture of azoxystrobin, a methoxyacrylate-type fungicide. Because of their wide use and economic importance, many methods of synthesis of chlorinated pyrimidines, especially 4,6-dichloropyrimidine, have been developed.
For example, U.S. Pat. No. 6,018,045 to Whitton et al. discloses a process for preparing 4,6-dichloropyrimidine that comprises treating 4,6-dihydroxyprimidine with phosphorous oxychloride (phosphoryl chloride) in the presence of a saturated hindered amine, the hydrochloride salt of a saturated hindered amine, or an unsaturated 5-membered nitrogen containing ring, or a mixture thereof. As a further step, the 4,6-dichloro-pyrimidine formed from these reactions is first directly extracted by, for example, a counter-current liquidxe2x80x94liquid separation technique. The process may also include mixing the residue that remains after the direct extraction with an aqueous solution of sodium or potassium hydroxide in order to liberate the saturated hindered amine or unsaturated 5-member nitrogen-containing ring (or mixture thereof), that was used in the process.
Other disclosures generally relating to preparation of 4,6-dichloropyrimidine by reacting 4,6-dihydroxypyrimidine with phosphorous oxychloride in the presence of a suitable base include Kenner et al. (J. CHEM. SOC., November 1943, pp. 574-575), Hull (J. CHEM. SOC., August 1951, p. 2214), British Patent GB2287466, and U.S. Pat. No. 5,583,226 to Stucky et al. In addition, U.S. Pat. No. 5,677,453 to Cramm et al. discloses synthesis of 4,6-dichloropyrimidines by reacting 4,6-dihydroxypyrimidines with excess phosphoryl chloride. In this type of synthesis, no base is added; however, an excess of phosphorus and chloride is used (with respect to the 4,6-dihydroxyprimidines). This excess is maintained by adding phosphorus trichloride and chlorine to the reaction mixture in amounts such that the phosphorus trichloride is maintained in excess over the chlorine. The process is carried out at temperatures of 60-110xc2x0 C. Distillation is advantageously used to purify the 4,6-dichloropyrimidines. Further, U.S. Pat. No. 5,750,694 to Jones et al. and WO 95/29166 (Zeneca Limited) disclose that 4,6-dichloropyrimidine can be prepared by reacting 4,6-dihydroxypyrimidine with phosgene (carbonyl chloride; carbon oxychloride; COCl2) in the presence of a suitable base. The base is preferably a tertiary amine and the base-to-phosgene ratio is preferably in the range of 10:1 to 1:10. Preferably, the process is carried out in a solvent or a mixture of solvents, with chlorinated solvents, ethers, and polar aprotic solvents being preferred.
Yanagida et al. (J. ORG. CHEM. 34(10):2972-2975, 1969) disclose preparation of specific 2,5-disubstituted-4,6-dichloropyrimidines by reacting an aliphatic nitrile compound of the general formula RCH2CN with itself in the presence of HCl and COCl2. According to the synthesis of Yanagida et al., R can be H, CH3, CH3CH2, CH3(CH2)2, CH2(CH2)3, (CH3)2CH, Cl, Cl(CH2)2, or CH3CH2O(CH2)2. The authors propose a reaction scheme in which 2,5-disubstituted-4,6-dichloropyrimidine synthesis proceeds through a 6-chloro-2,5-disubstituted-4(3H)pyrimidone intermediate. Further reaction of these intermediates with phosgene gives the corresponding 2,5-disubstituted-4,6-dichloropyrimidines. The authors also propose a second reaction scheme for formation of 2,5-disubstituted-4,6-dichloropyrimidines from aliphatic nitrites. In the second scheme an aliphatic nitrile condenses with itself in the presence of HCl to form an amidine, which is then converted in the presence of phosgene to ultimately give a 2,5-disubstituted-4,6-dichloropyrimidine. Further, Yanagida et al. (J. BULL. CHEM. SOC. JAPAN 46:299-302, 1973) discloses reaction of N-(xcex1-chloroalkenyl)alkylamidine hydrochlorides with phosgene to create 4,6-dichloro-2,5-disubstituted pyrimidines.
However, none of these references disclose the preparation of chlorinated pyrimidines that are not substituted in the 2 position, including 4,6-dichloropyrimidine itself. Synthesis of chlorinated pyrimidines that are not substituted in the 2-position requires cross-condensation of two distinct imidoyl chloride compounds, with one of the imidoyl chloride components being derived from either hydrogen cyanide or formamide.
Because of the economic importance of 4,6-dichloropyrimidine in the production of agricultural and medical compounds, as well as its importance in production of tools for scientific research, new, straightforward, rapid, and cost-effective methods for synthesis of this chlorinated pyrimidine are continually being developed.
The present invention provides a method of synthesizing 4,6-dichloropyrimidine, 4-chloro-6-hydroxypyrimidine, 5-substituted-4-chloro-6-hydoxypyrimidines, and 5-substituted-4,6-dichloropyrimidines. The method is less expensive and simpler than those methods currently available. In general, the method of preparing these compounds according to the present invention comprises cross-condensation of formamidoyl chloride with a distinct imidoyl chloride compound in the presence of phosgene (COCl2) and HCl and, optionally, in the presence of solvent. For present purposes, xe2x80x9cdistinct imidoyl chloride compoundxe2x80x9d refers to compounds with different hydrocarbyl groups, preferably different alkyl groups, than formamidoyl chloride, for example, acetamidoyl chloride. The present invention also includes use of compounds which can be easily converted into imidoyl chlorides under reaction conditions, for example, nitriles like acetonitrile which react with HCl to give the imidoyl chloride. In the case of formamidoyl chloride, the starting materials can optionally be HCN and HCl; or formamide and COCl2.
In one embodiment, the synthesis method of the present invention includes cross-condensation of imidoyl chloride compounds derived from a nitrile and hydrogen cyanide. For example, the method of the invention can include reacting acetonitrile and hydrogen cyanide with hydrogen chloride and phosgene to form 4,6-dichloropyrimidine.
In other embodiments of the invention, the method includes cross-condensation of imidoyl chloride compounds derived from an alkylamide and hydrogen cyanide. For example, the method of the invention can include reacting acetamide and hydrogen cyanide with hydrogen chloride and phosgene to form 4,6-dichloropyrimidine.
In further embodiments of the invention, the method includes cross-condensation of imidoyl chloride compounds derived from a nitrile and formamide. For example, the method of the invention can include reacting acetonitrile and formamide with hydrogen chloride and phosgene to form 4,6-dichloropyrimidine.
In other embodiments of the invention, the method includes cross-condensation of imidoyl chloride compounds derived from an alkylamide and formamide. For example, the method of the invention can include reacting acetamide and formamide with hydrogen chloride and phosgene to form 4,6-dichloropyrimidine.
The solvent can optionally be an inert organic solvent, for example chlorobenzene, or an excess of one of the raw materials, for example acetonitrile.
Reaction temperatures can be in the range of 0xc2x0 C. to 160xc2x0 C., preferably 60xc2x0 C. to 120xc2x0 C., and most preferably 100xc2x0 C. to 110xc2x0 C.
The reaction is typically carried out in a sealed vessel under autogenous pressure of 0 to 800 psig, preferably 100 to 300 psig, and most preferably 150 to 250 psig.
The process of the invention results in preferential formation of the desired chlorinated pyrimidine (i.e., the cross condensation product) relative to formation of the chlorinated pyrimidine substituted at the 2 position (i.e., the self condensation product). In particular, it is surprising to observe that reaction of formamidoyl chloride or its equivalents with acetamidoyl chloride or its equivalents favors the production of 4,6-dichloropyrimidine, the cross-coupling product, over the production of 2-methyl-4,6-dichloropyrimidine, the self condensation product from acetonitrile. For example, an equimolar mixture of the two (formamidoyl chloride or equivalent with acetamidoyl chloride or equivalent) is expected to give the statistical 1:1 distribution of 4,6-dichloropyrimidine and 2-methyl-4,6-dichloropyrimidine. In contrast a distribution of approximately 10:1 is typically observed favoring 4,6-dichloropyrimidine itself. Similarly, when a large excess of acetonitrile relative to formamidoyl chloride is used, the product ratio indicates that the cross-condensation product is preferentially formed. For example, when a 37:1 molar ratio of acetonitrile to formamidoyl chloride is used, the ratio of 4,6-dichloropyrimidine to 2-methyl-4,6-dichloropyrimidine is approximately 1:1.4. In a statistical distribution of products, a ratio of 1:37 would be expected.
All of the embodiments described above can also be used for the preparation of 4-chloro-6-hydroxypyrimidine by limiting the amount of phosgene or by conducting the reaction at low temperatures.
All of the embodiments described above can also be used for the preparation of certain 5-substituted-4,6-dichloropyrimidines by using appropriately substituted amides or nitrites. For example, the method of the invention can include reacting butyronitrile and formamide with hydrogen chloride and phosgene to form 5-ethyl-4,6-dichloropyrimidine.
All of the embodiments described above can also be used for the preparation of 5-substituted-4-chloro-6-hydroxypyrimidine by using appropriately substituted amides or nitrites and by limiting the amount of phosgene or by conducting the reaction at low temperatures.
The chlorinated pyrimidines produced by the method of the invention can be used to synthesize commercially or medically important compounds. For example, the chlorinated pyrimidines, especially 4,6-dichloropyrimidine, can be used to make pesticides, and/or pharmaceuticals, such as nucleoside analogs and compounds that are active on the central nervous system (CNS) of animals and humans.
Additional objects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. The objects and advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims.